Several million individuals suffer from bone and joint dysfunction that adversely impacts individual quality of life, medical costs associated with treatment, and economic productivity to the individual, state and federal governments. Although advancements have been made in surgically correcting bone and joint disease with artificial prostheses, each procedure has inherent limitations. By regenerating natural tissue, tissue engineering offers significant advantages over artificial joint replacement. Due to these advantages, the economic and technology transfer benefits of tissue engineering are substantial. Business week (7-27-98) cited a study that $400 billion per year were spent to correct organ and tissue failure, half of the US national health care budget. We will develop a gene therapy-directed tissue reconstruction system based on rapid fabrication of designed scaffolds that deliver appropriate genes for bone and cartilage regeneration. This project integrates engineering techniques including imaging, computational design and 3-D micro/macro material fabrication with biological techniques of gene transfer and genetic engineering of mesenchymal stem cells to produce engineered materials/biologic constructs for tissue regeneration. These constructs will be able to regenerate tissues lost to trauma, congenital deformities and chronic degenerative disease. The hypothesis underlying this proposed study is that both bone and cartilage can be produced on a single bioengineered scaffold by gene transfer of appropriate morphogenetic signal in vivo. This hypothesis will be tested in two specific aims: 1) To develop materials/biologic constructs for gene therapy-induced bone and cartilage regeneration; and 2) To determine the relative efficacy of in vivo and ex vivo gene therapy strategies to gain spatial control over regeneration of bone and cartilage tissue as well as the corresponding bone-cartilage interface in bioengineered scaffolds. Bone and cartilage formation in our anatomic-specific designed bioengineered materials will facilitate innovative strategies for the reconstruction of human joints.